HLA class II alleles in the DQA1, DQB1, DRB1, and DPB1 genes were investigated in Japanese patients with myasthenia gravis (MG) by digestion of polymerase chain reaction amplified DNAs with allele specific restriction endonucleases (PCR-RFLP). A significantly higher frequency of DQB1*03, which includes *0301, *0302, *0303 and determines the serological DQ3 specificity, was observed in feamle patients less than 30 years in age at onset of disease compared with healthy controls (90.5 vs. 53.2%). This study also confirms the high incidence of DPB1*0201 in early-onset female patients compared to the controls (85.7 vs. 40.3%). Moreover, 81.0% of the early onset female patients were found to carry both DQB1*03 and DPB1*0201, compared to 17.7% of the controls. Since DQB1*03 and DPB1*0201 are not in linkage disequilibrium, both these alleles are supposed to be synergistically involved in disease development in early-onset female MG. In contrast, no obvious association of HLA-DQA1, DQB1, DRB1 and DPB1 alleles with either late-onset patients or patients with thymoma was observed. Clearly, the genetic background of Japanese females with early onset MG is different from that of other patients with MG.